Certain thiazine-2-thione compounds and method of preparing same

ABSTRACT

Certain thiazolidine- and thiazine-2-thione compounds, including 5-carboxythiazolidine-2-thione and 3,4-tetramethylene-4H,5,6dihydro-1,3-thiazine-2-thione, and methods for preparing same are disclosed.

United States Patent Reece et a1.

[451 Oct. 10, 1972 [54] CERTAIN THIAZINE-Z-THIONE COMPOUNDS AND METHODOF PREPARING SANIE [72] Inventors: Jack E. Reece, Willemie, Minn.;George B. Fozzard, Bartlesville,

Okla.

[73] Assignee: Phillips Petroleum Company [22] Filed: Oct. 19, 1970 [21]Appl. No.: 82,175

[52] US. Cl ..260/243 R, 424/246, 260/306.7, 424/270 [51] Int. Cl...C07d 93/08 [58] Field of Search ..260/243 R [56] References CitedUNITED STATES PATENTS 2,514,004 7/ 1950 Mathes et al. ..260/2432,727,035 12/1955 Bowers et a1. ..260/243 2,845,339 7/1958 Bluestone..260/243 X 2,909,460 10/1959 Gaertner ..260/243 X 2,920,996 1 1960Bluestone ..260/243 X 3,085,046 4/ 1963 Cummins ..260/243 X 3,126,378 3/1 964 Cummins ..260/243 3,346,638 10/ 1967 Metlesics et a]. ..260/243 X3,361,715 l/1968 Vogt et a1. ..260/243 X 3,373,158 3/1969 Schorr et a1...260/243 3,398,146 8/1968 Schorr et al. ..260/243 3,400,1 l9 9/1968Wenner et a1. ..260/243 3,435,032 3/ 1969 Watanabe et al. .....260/243 XPrimary Examiner-John M. Ford Attorney-Young and Quigg [57] ABSTRACTCertain thiazolidineand thiazine-2-thione compounds, including5-carboxythiazolidine-2-thione and 3 ,4-tetramethylene-4H,5 ,6-dihydro-1 ,3-thiazine-2- thione, and methods for preparing same are disclosed.

5 Claims, No Drawings CERTAIN THlAZlNE-Z-THIONE COMPOUNDS AND METHOD OFPREPARING SAME This invention relates to the thiazolidineandthiazine-Z-thione compounds characterized by the wherein each R ishydrogen or lower alkyl group, e.g.,

containing from one to six, preferably one to four, carbon atoms, andthe total number of carbon atoms in said R substituents is'not more than12, preferably not more than 10; and methods for preparing same.

Examples of compounds of the invention within the scope of the aboveformulas l and [I include, among others, the following:S-carboxythiazolidine-2-thione; -carboxy-4-methylthiazolidine-2-thione;S-carboxy- 4,4-dimethylthiazolidine-2-thione; 5-carboxy-4-ethylthiazolidine-2-thione; 5-carboxy-4-hexylthiazolidine-Z-thione;5-carboxy-4-methyl-4- propylthiazolidine-Z-thione;5-carboxy-4-sec-butylthiazolidine-2thione;5-carboxy-5-butyl-4,4-dibutylthiazolidine-Z-thione;3,4-tetramethylene-4H,5,6- dihydrol ,3-thiazine-2-thione; 3,4-tetramethylene- 4H,5-methyl-5 ,6-dihydro-l ,3-thiazine-2-thione; 3,4-( 3- hexyl )-tetramethylene-4H ,5 ,6-dihydrol ,3-thiazine-2- thione;3,4-(3-butyl)tetramethylene- 4l-l,5-ethyl-5,6-dihydro-l,3-thiazine-2-thione; 3,4-(3-hexyl )tetramethylene-4l-l ,5-(sec-butyl )-5 ,6-dihydro-l ,3- thiazine-2-thione;3,4-(3-pentyl-4-ethyl)- tetramethylene-4H ,5 -pentyl-5 ,6-dihydrol,3-thiazine- 2-thione; and the like.

The compounds of the invention can be prepared by any suitable method.

One presently preferred method for preparing the compounds representedby the above formula I comprises reacting an alkali metal hydroxide, anappropriate aminomercaptan, and carbon disulfide. Said alkali metalhydroxide can be any of the hydroxides of sodium, potassium, rubidium,cesium, and lithium, or mixtures thereof. However, for reasons of costand availability, sodium and/or potassium hydroxide are preferred. Saidaminomercaptan can be any suitable aminomercaptan capable of reactingwith a said alkali metal hydroxide and carbon disulfide to give aproduct within the scope of said formula I. For example, cysteinehydrochloride hydrate will react with sodium or potassium hydroxide andcarbon disulfide to yield 5- carboxythiazolidine-Z-thione.

Said reaction of alkali metal hydroxide, aminomercaptan, and carbondisulfide is preferably carried out in an aqueous reaction admixture ofthe reactants. Any suitable mol ratio of said reactants can be utilized.Preferably, a mol ratio of alkali metal hydroxide to aminomercaptanwithin the range of from to 2, more preferably 5 to 3, can be utilized.Preferably, a mol ratio of carbon disulfide to aminomercaptan within therange of 10 to l, more preferably 2 to 1.2, can be utilized. Thereaction temperature is not critical. The reaction(s) take place readilyat ambient temperatures,

e.g., 60 to ll0 F. However, it is within the scope of the invention toemploy reaction temperatures outside said range. The reaction(s) isusually carried out at atmospheric pressure, but the use ofsubatmospheric or superatmospheric pressures is within the scope of theinvention. The reaction(s) is preferably carried out with stirring ofthe reaction admixture for any suitable reaction period, e.g., from 4 to48, preferably 8 to 30, hours. However, reaction periods outside saidranges can be employed.

One presently preferred method for preparing the compounds representedby the above formula II comprises acidifying an appropriate(hydroxyalkyl)- piperidine with HCI, preferably gaseous, so as to obtainthe corresponding (hydroxyalkyl)piperidine hydrochloride. Saidacidification is preferably carried out in the presence of an inertsolvent. Any suitable solvent which is a solvent for the reactants andwhich is inert with respect to the reactants and the reaction productscan be used in the practice of the invention. Examples of said solventsinclude the organic solvents such as benzene, toluene, the xylenes,cyclohexane, and the like. Said (hydroxyalkyl)piperidine hydrochlorideis reacted with a halogen-substitution agent, preferably an agentwherein the halogen is chlorine or bromine, and which is capable ofconverting said hydroxyalkyl substituent to the corresponding haloalkylsubstituent. The resulting (haloalkyl)piperidine hydrochloride is thenrecovered from the reaction mixture. Said recovered(haloalkyl)piperidine'hydrochloride is then reacted with an alkali metalhydroxide and carbon disulfide, preferably in an aqueous reactionmedium. Said alkali metal hydroxide can be any of the hydroxides ofsodium, potassium, rubidium, cesium, and lithium, or mixtures thereof.However, for reasons of cost and availability, sodium and/or potassiumhydroxides are preferred. Said (hydroxyalkyl)piperidine hydrochloridecan be any suitable such compound capable of undergoinghalogen-substitution to give the corresponding (haloalkyl)piperidinehydrochloride. Said halogen-substitution agent can be any suitablehalogen-substitution agent such as thionyl chloride, phosphoruspentachloride, and the like, which is capable of reacting as described.For example, said (hydroxyalkyl)piperidine hydrochloride can be2-(Z-hydroxyethyl)piperidine which will react with, for example, thionylchloride to give 2-(2-chl0roethyl)piperidine hydrochloride. Said(haloalkyl)-piperidine hydrochloride will react with an alkali metalhydroxide and carbon disulfide to yield 3 ,4-tetramethylene-4H,5,6-dihydro-l ,3-thiazine-2- thione. Said acidification is preferablycarried out at ambient temperatures, e.g., 60 to F., but tem pcraturesoutside this range can be used. The reaction of the halogen-substitutionagent with the (hydroxyalkyl)piperidine to convert the hydroxyalkylsubstituent to the corresponding haloalkyl substituent can beconveniently carried out at the normal refluxing temperature of thereaction mixture. After cooling the reaction mixture, volatile materialsare preferably removed at a reduced pressure. The resulting solidresidue is then preferably dissolved in water and then reacted with thecarbon disulfide and alkali metal hydroxide. Temperature is not criticalin this reaction. The reaction can be carried out at ambienttemperatures but is preferably carried out at the normal refluxingtemperatures of the norm.

reaction mixture. The reaction mixture is then acidified, for examplewith aqueous HCl, and volatile materials removed at reduced pressure.The remaining product can be purified and crystallized in known manner,e.g., dissolving in an alcohol and recrystallizing. Any suitable'molratio of said reactants can be utilized. Preferably, a mol ratio ofhalogen-substitution agent to piperidine hydrochloride will be withinthe range of from 4 to 1.2, more preferably 2 to 1.4. Preferably, themol ratio of the alkali metal hydroxide to the (haloalkyl)piperidinehydrochloride will be within the range of from to 1.6, more preferably2.5 to 1.7. Preferably, the mol ratio of the carbon disulfide to said(haloalkyl)piperidine hydrochloride will be within the range of from 4.0to 1.2, more preferably 2 to 1.4. All of the reactions are preferablycarried out with stirring of the reaction mixture and for any suitablereaction period. For example, the reaction period for thechlorine-substitution reaction can be within the range of from 1 to 4,preferably 1.5 to 3 hours, and the reaction period for the reaction ofthe carbon disulfide and alkali metal hydroxide" I with the(haloalkyl)piperidine hydrochloride can be in the range of from 3 to 12,preferably 4 to 8 hours. However, reaction periodsoutside said rangescan be employed.

The examples given hereinafter will serve to further illustrate theinvention. Examples 1 and Il illustrate the preparation of compounds ofthe invention. Reactants used in preparing the compounds of theinvention are known availablematerials or can be readily prepared bymethods known in the art for preparing such materials. Examples 111 andIV show that compounds of the invention are useful as analgesics. Saidcompounds are generally administered to mammalian patients in dosages offrom 1 to 100 mg/kg of body weight daily, either in single or divideddoses over a period of 24 hours.,While the compound isactive by variousroutes, oral administration is usually preferred.

The compound can be formulated into various pharmaceuticaldosage formssuch as tablets, capsules, pills, and the like, for immediate orsustained release, by combining it with a suitable pharmaceuticallyacceptable carrier or diluent according to methods well known in theart. Such dosage forms may additionally include excipients, .binders,fillers, flavoring and sweetening agents and other therapeutically inertingredients necessary in the formulation of the desired pharmaceuticalpreparation.

EXAMPLE 1 Preparation of 5-Carboxythiazolidine-2-thione Sodium hydroxide(40 g., 1.0 mol), cysteine hydrochloride hydrate (50 g., 0.285 mol) andcarbon disulfide (30 g., 0.4 mol) were added in that order to 200 ml.water at room temperature. This mixture was stirred for 24 hours. At theend of this period, the reaction mixture was acidified to pH 6 withhydrochloric acid and evaporated to yield a yellow foam. Trituration ofthis foam with concentrated hydrochloric acid caused crystallization tooccur. The white solid thus obtained was recrystallized from 6 Nhydrochloric acid to yield 12.2 g. (21.2 percent) of5-carboxythiazolidine-2- thione, m.p. "l 831 84 C. with decomposition.

Anal.: Calcd. for C H,O,NS,: C, 29.5; H, 3.1; N, 8.6;

S, 39.3 Found: C, 29.6;H, 3.2; N, 8.7; S, 39.5

EXAMPLE [1 Preparation of 3.4-Tetramethylene-4H,5,6-dihydro- -th izi1e2i j929 2-(2-l-lydroxyethyl)piperidine g., 0.775 mol) was dissolvedinbenzene and acidified by the introduction of excess gaseous HCl.Thionyl chloride g., 1.25 mol) was then added slowly and this mixturewas stirred at gentle reflux for 2 hours. After cooling, volatiles wereremoved at reduced pressure. The resulting solid residue was dissolvedin approximately 200 ml. water and transferred to another reactionflask. Carbon disulfide (100 g., 1.25 mol) was added and the resultingcombination stirred vigorously as sodium hydroxide (50 g., 150 mol,dissolved in 300 ml. water) was added. This mixture was-stirred atgentle reflux for 6 hours. The mixture was then acidified with 6 N HCland volatiles were removed at reduced pressure. The solid residueresulting was dissolved in boiling isopropyl alcohol and filtered freeof insolubles. The crude product which crystallized from this filtratewas then. recrystallized once from aqueous ethanol and once fromabsolute ethanol to isolate 31 g. of 3,4

tetramethylene-4H,5,6-dihydro-1 ,3-thiazine-2-thione, m.p. 80.5-8 1 .5C.

Anal.: Calcd. for C H, NS,: C, 51.3;H, 7.0; N, 7.5; S,

34.2 Found: C, 51.4; H, 6.8; N, 7.3; S, 34.4

EXAMPLE Ill The analgesic properties of 5-carboxythiazolidine-2- thionewere established by the acetic acid writhing test according to themethod of. B. A. Whittle, Brit J- Pharmcol. 22, 246-253 (1964). By thistest, 5-carboxythiazolidine-2-thione afforded 29 percent analgesiainmice at a dose level of 50 mg/kg.

EXAMPLE IV The analgesic properties of 3,4-tetramethylene-4H,5,6-dihydro-l,3-thiazine-2-thione were established according to theabove-mentioned acetic acid writhing test. The EDSO, i.e., the reductionof the response in 1 treated animals to 50 per cent of the value incontrol animals, of the'compound in mice is 13 mg/kg. The edemainhibition activity was established in the carragcenan-induced rat pawedema test according to the method of C. A. Winter, et al, Proc. Soc.Exp. Biol. Med., 111, 544-547 (1962). The ED25, defined corresponding tothe above, of the compound in mice is 60 mg/kg. The LD50 in mice is 315mg/kg.

While certain embodiments of the invention have been described forillustrative purposes, the invention is not limitedthereto. Variousother modifications or embodiments of the invention will be apparent tothose skilled in the art in view of this disclosure. Such modificationsor embodiments are within the spirit and scope of the disclosure.

' We claim:

1. The thiazine-2-thione compounds characterized the structural formula:W

R R R R hydrochloride with a halogen-substitution agent wherein thehalogen is chlorine or bromine and which is capable of converting saidhydroxyalkyl substituent to the corresponding haloalkyl substituent;recovering the resulting (haloalkyl)-piperidine hydrochloride from theresulting reaction mixture; and reacting said recovered(haloalkyl)piperidine hydrochloride with an alkali metal hydroxide andcarbon disulfide.

4. A method according to claim 3 wherein: said (hydroxyalkyl)-piperidineis 2-(2-hydroxyethyl)piperidine and is acidified in the presence of aninert organic solvent; said (hydroxyalkyl)piperidine hydrochloride is2-(2-hydroxyethyl)piperidine hydrochloride; said halogen-substitutionagent is thionyl chloride and is reacted with said hydrochloride toobtain (haloalkyl)piperidine hydrochloride which is 2'-(2-chloroethyl)piperidine hydrochloride; said alkali metal hydroxide issodium hydroxide or potassium hydroxide and is reacted with said 2-( 2-chloroethyl)piperidine hydrochloride in an aqueous reaction medium; anda thiazine-Z-thione compound reaction product identified as3,4-tetramethylene- 4l-l,5 ,6-dihydro-1,3-thiazine-2-thione is recoveredfrom said aqueous reaction medium.

5. A method in accordance with claim 4 wherein: the mo] ratio of saidthionyl chloride to said 2-(2-hydroxyethyl)piperidine hydrochloride iswithin the range of from 4 to 1.2; the mo] ratio of said alkali metalhydroxide to said 2-( 2-chloroethyl)piperidine hydrochloride is withinthe range of from 5 to 1.6; and the mo! ratio of said carbon disulfideto said 2-(2-chloroethyl)- piperidine hydrochloride is within the rangeof from 4.0 to 1.2.

2. A thiazine-2-thione compound in accordance with claim 1, andidentified as 3,4-tetramethylene-4H,5,6-dihydro-1,3-thiazine-2-thione.3. A method for preparing the thiazine-2-thione compounds of claim 1,which method comprises: acidifying an appropriate(hydroxyalkyl)piperidine with gaseous HCl to obtain the corresponding(hydroxyalkyl)piperidine hydrochloride; reacting said piperidinehydrochloride with a halogen-substitution agent wherein the halogen ischlorine or bromine and which is capable of converting said hydroxyalkylsubstituent to the corresponding haloalkyl substituent; recovering theresulting (haloalkyl)-piperidine hydrochloride from the resultingreaction mixture; and reacting said recovered (haloalkyl)piperidinehydrochloride with an alkali metal hydroxide and carbon disulfide.
 4. Amethod according to claim 3 wherein: said (hydroxyalkyl)-piperidine is2-(2-hydroxyethyl)piperidine and is acidified in the presence of aninert organic solvent; said (hydroxyalkyl)piperidine hydrochloride is2-(2-hydroxyethyl)piperidiNe hydrochloride; said halogen-substitutionagent is thionyl chloride and is reacted with said hydrochloride toobtain (haloalkyl)piperidine hydrochloride which is2-(2-chloroethyl)piperidine hydrochloride; said alkali metal hydroxideis sodium hydroxide or potassium hydroxide and is reacted with said2-(2-chloroethyl)piperidine hydrochloride in an aqueous reaction medium;and a thiazine-2-thione compound reaction product identified as3,4-tetramethylene-4H,5,6-dihydro-1,3-thiazine-2-thione is recoveredfrom said aqueous reaction medium.
 5. A method in accordance with claim4 wherein: the mol ratio of said thionyl chloride to said2-(2-hydroxyethyl)piperidine hydrochloride is within the range of from 4to 1.2; the mol ratio of said alkali metal hydroxide to said2-(2-chloroethyl)piperidine hydrochloride is within the range of from 5to 1.6; and the mol ratio of said carbon disulfide to said2-(2-chloroethyl)-piperidine hydrochloride is within the range of from4.0 to 1.2. 12.